It is estimated that mental disorders account for 10 percent of the global burden of disease with four disorders ranking among the 10 leading causes of disability worldwide: namely, unipolar major depression, bipolar disorder, schizophrenia and obsessive-compulsive disorder (National Institute of Mental Health, Report of the National Advisory Mental Health Council Behavioral Science Workgroup, March 2000). Unfortunately, the fundamental basis by which neurobiologic function translates into behaviors such as cognition, emotion, motivation, development, personality and social interaction are (at present) largely unknown.
Delivery of drugs from the blood and into neural tissues (neuraxial delivery) is a key aspect complicating clinical rehabilitation and intervention techniques. The blood brain barrier effectively limits access of many classes of known and potentially useful pharmaceutical agents. For instance, in Parkinson's disease it has long been understood that the disease results from a defect in dopamine biosynthesis, but it has proven exceptionally difficult to effect proper delivery of therapy across the blood brain barrier into affected nigrostriatal tissues. Catecholamines including dopamine, norepinephrine and epinephrine are produced by chromaffin cells in the adrenal medulla responding as a specialized ganglion to sympathetic enervation from preganglionic fibers of the splanchic nerve. However, catecholamines do not cross the blood-brain barrier, hence, the need for synthesis within the CNS. Although metabolic replacement therapy in Parkinson's might theoretically be effected with L-Dopa, the precursor of dopamine and a compound, which readily crosses the blood-brain barrier, the compound is highly unstable and rapidly inactivated in blood.
L-dopa, Levodopa, Cardiodopa (an inhibitor of dopa decarboxylase), Deprenyl (inhibiting dopamine degrading monoamine oxidase), Sinemet (a controlled release form of Levodopa) and their combinations and derivatives suffer from many major disadvantages common also in certain other drugs which might be used in neuraxial therapies, e.g. poor aqueous solubility, poor brain penetrability, relatively short half-lives, dosing fluctuations and numerous side effects. Observed side effects accompanying chronic use in Parkinson's patients include motor fluctuation, dysfunctions, peak-dose dyskinesia, requirements for frequent dosing, involuntary movements, psychosis, confusion, visual hallucinations, bradykinesia, rigidity, tremors, gastrointestinal and gentiourinary dyantonomia, hypotension and cognitive decline (Hurtig, 1997). Often after 3-5 years of treatment patients reportedly develop complex dose-related unpredictable response fluctuations leading to a progressive decrease in therapeutic efficacy and also possible onset of serious side effects such as abnormal involuntary movements, end-of-dose deterioration and abrupt near instantaneous on-off changes in patient disability. “Adaptation” by neural tissues to chronic administration is complex, and may include down-regulation of dopamine receptor expression as well as metabolic changes in post-striatal neurons. In addition to these neurologic side effects, metabolism of oral dopa compounds to dopamine in the stomach and gastrointestinal tract (even in the presence of decarboxylase inhibitors) can often lead to unwanted side effects including severe nausea and hypotension. Levodopa methyl and ethyl esters given orally suffer many of these same problems. Thus, all current therapies for treating Parkinsonism suffer from serious side effects, bioavailability problems, or both, and there has been a long-felt need for improved pharmaceutically active agents for metabolic replacement therapy in Parkinson's and related diseases (Hurtig, 1997).
In pharmacologic studies conducted over the past 20 years, the results seem to suggest relatively stringent structural requirements for activation of the D1 receptors, particularly in regard to any nitrogen atoms present in the compound (e.g., see Seiler et al., 1991; Berger et al., 1989; Brewster et al., 1990; Kaiser et al., 1982; Dandridge et al., 1984; Brewster et al. 1990; Weinstock et al., 1985; Riggs et al.; Seiler et al., 1982; Shah et al., 1996; Knoerzer et al., 1994). In addition, the nature of the terminal group (i.e., amino), or presence or length of an n-alkyl chain (Iorio et al., 1986) may reportedly influence binding interactions at D1 sites. Based on experience with different pharmacophores, several receptor models have been proposed (Seiler and Markstein, 1989; Petersson et. al., 1990; Brewster et. al., 1990; Knoerzer et. al., 1994; Snyder et. al., 1995; Minor et. al., 1994). By comparison, pharmacologic studies of D2-like receptors suggest somewhat less rigid overall structural requirements, but also restrictions around any nitrogen atoms (e.g., see McDermed et al. 1979; Freeman and McDermed, 1982; Liljefors et al., 1986; van de Waterbeemd et al., 1987).
The Na+/Cl− dependent dopamine transporter, DAT1, granule system mediates calcium-dependent outward dopamine release into the synaptic cleft and inward energy-dependent dopamine vesicular re-uptake into the cytoplasm of presynaptic neurons. Loading of biosynthetic dopamine into granules is effected by the vesicular monoamine transporter (VMAT2; reviewed in Miller et al., 1999). DAT may also control movements of other monoamines in brain tissues. Cocaine, amphetamines, phencyclidine and certain anti-depressants and uptake inhibitors interfere with dopamine transport by DAT (e.g., see Jones et al., 1999; Giros et al., 1992). DAT function may be regulated by steroid hormones, has second order dependence on Na+ (Earles et al., 1999) and may be coupled (or uncoupled) to modulatory second messenger systems, (e.g., down-regulation of DAT accompanying activation of protein kinase C by phorbol esters), and ionic currents (Melikian et al., 1999; reviewed in Figlewicz, 1999). Radiotracer imaging methods have been used to localize DAT (e.g., within the nucleus accumbens and mid-brain regions) and D1 and D2 receptors (e.g., in nigrostrial pathways) in the brains of normal subjects, as well as in patients with Parkinson's disease and neuropsychiatric diseases such as schizophrenia (reviewed in Verhoeff, 1999). Structure activity studies of antagonists have suggested that: (i) the DAT transporter may be sensitive to N-substitution (Choi et al., 2000); (ii) N-phenyl-substituted analogues may inhibit transport (Prakash et al., 1999; Husbands, et al., 1999); (iii) certain energetically unfavored boat conformations of rings may have high affinity for DAT (Prakash et al., 1999); (iv) structural rearrangement of the DAT protein may occur and be required for inward transport (Chen et al., 2000;); (v) the DAT protein contains an endogenous Zn2+ binding site (Loland et al., 1999); (vi) DAT transporter function is sensitive to aromatic substitutions (Husbands, et al., 1999); and, (vii) apparent ordered kinetics for DAT transporter function is Na+ binding first, then dopamine and then Cl−.
Several tissue enzyme systems exist for altering catecholamines, including dopamine. Monoamine oxidases, MAO-A in neural tissues and MAO-B in other tissues including stomach and intestine, are oxioreductases that deaminate dopamine and other catecholamines with preferential activity manifest for 2-phenylethylamine and benzylamine. Catechol-O-methyltransferase is a cytosolic enzyme that catalyzes addition of a methyl group, usually at the 3 position of a benzyl ring. O-methoxylated derivatives may be further modified by conjugation with glucuronic acid. Non-neuronal dopamine transporter uptake mechanisms may also exist, e.g., in kidney (Sugamori et. al., 1999).
Oral delivery of drugs constitutes special chemical challenges, i.e., general simultaneous requirements for intestinal penetration, blood borne delivery, blood-brain-barrier penetrability and maintenance of functional (receptor binding and/or metabolic) utility. CNS active drugs constitute yet additional special and challenging problems, i.e., low pH stability (or protection) and intestinal transport. Intestinal intracellular transport mechanisms for amino acids, vitamins and sugars are varied. Glucose transport has recently been reviewed (Takata et. al., 1997). Transport mechanisms for glucose include intestinal transport vesicles and Na+/glucose co-transporters (SGLTs), i.e., driving active transport of glucose and galactose across the intestinal brush border by harnessing Na+ gradients across the cell membrane. Net rates of vesicle transport and exocytosis have been estimated to be in the range of 10 thousand to 1 million per second (Wright et. al., 1997). Missense mutations in SGLT1 reportedly result in potentially lethal inability to transport glucose and galactose (Martin et. al., 1996). Certain sugar specificity's, structural requirements and capabilities of Na+-dependent glucose transport carriers have been investigated with impure receptor membrane preparations, and/or mixtures of receptors, with the findings that the glucosyl transporter in human erythrocytes (i.e., GLUT1): (i) seems to require that the ring oxygen atoms at positions C1, C3, C4, and possibly C6, be capable of forming hydrogen bonds with the transporter protein, and (ii) a hydrophobic group at C5 may increase affinity for the transporter (Barnett et al., 1973). Intestinal glucose transporter mechanisms reportedly prefer: (i) β-anomers to α-anomers; (ii) β-D-glucose to β-D-galactose; and, (iii) β-glucoside>α-glucoside>β-galactoside>α-galactoside. The α-anomers of glucose and galactose were reportedly hydrolyzed to their aglycone constituents during a non-Na+-dependent desglucosylation transport (Mizuma et. al., 1992, 1993, 1994). Apparently unrelated studies of antiviral glycosides have reportedly found that: (i) C1 phenyl-substituted glycosides and para-substituted butyl-phenyl derivatives may inhibit glucose transporters (Arita et al., 1980); (ii) C1O-acyl glycoside derivatives with alkyl chains or carbonyl groups (as an aglycone substituent) may act as non-penetrating inhibitors of glucose transport (Ramaswamy et al., 1976); and (iii) 1-5-anhydroglucitol and 6-deoxyglucose may be transportable (Alvarado et al., 1960). Thus, like dopaminergic receptor binding, the art suggests that special chemical structural requirements may exist for intestinal transport.
Metabolic replacement therapy using compounds that are endogenously converted to dopamine, e.g., Levodopa, results in stimulation of both D1-like and D2-like dopaminergic families of receptors. While agonists are theoretically superior to Levodopa (i.e., because they should not be dependent on enzymatic conversion), in clinical use they have been shown to lack the therapeutic potency of Levodopa. Direct acting D2 agonists (e.g., bromocriptine, lisuride and pergolide) have also shown limited efficacy in monotherapy and are primarily used as add-on therapy to L-Dopa.
Dopamine administered intravenously, while not crossing the blood brain barrier, binds D1-like and D2-like dopamine receptors in the periphery and is reportedly useful in certain treatments for peripheral defects such as congestive heart failure and hypertension (e.g., Kuchel, 1999). However, it's utility is also limited by bioavailability problems. Thus, there has also been a long-standing need for improved dopaminergic catechol agonists with improved bioavailability and penetrability of myelinated nerves, i.e., for peripheral use in treatments of e.g. hypertension and congenital heart diseases.
Success in development of a candidate neuropharmaceutical agent may often turn on issues of whether receptor binding activity can be retained while optimizing for intestinal transport, pharmacologic half-life in blood and blood brain barrier penetrability. For example, pharmacologic studies conducted over at least the past 20 years, seem to suggest relatively stringent structural requirements for activation of D1 receptors, particularly in regard to any nitrogen atoms present in a compound (e.g., see Seiler et al., 1991;Berger et al., 1989; Brewster et al., 1990; Kaiser et al., 1982; Dandridge et al., 1984; Brewster et al. 1990; Weinstock et al., 1985; Riggs et al.; Seiler et al., 1982; Shah et al., 1996; Knoerzer et al., 1994). In addition, the nature of any terminal group (i.e., amino), or presence or length of an N-linked alkyl chain (Iorio et. al., 1986) may reportedly influence binding interactions at D1 sites. Based on experience with different pharmacophores, several receptor models have been proposed (Seiler and Markstein, 1989; Petersson et. al., 1990; Brewster et. al., 1990; Knoerzer et. al., 1994; Snyder et. al., 1995; Minor et. al., 1994). Thus, relatively stringent chemistry may be imposed upon a potential drug candidate by just the requirement for receptor binding at a single class of receptor.
Unfortunately, even within a class, receptors may be structurally (and functionally) heterogeneous. For example, molecular cloning studies have identified several different genes encoding dopamine receptors. D1-like receptors, recognized pharmacologically by the SCH23390 specific agonist, activate adenylate cyclase resulting in increased intracellular cAMP. Two gene products have been identified D1A and D1B, (also identified pharmacologically as D5). D1B/D5 appears responsible for SCH23390 specific agonist activity. D2-like dopamine receptors, recognized pharmacologically by spiperone and sulpride specific agonists, appear to be encoded by three genes with multiple possible splice variants expressed in different brain regions, i.e., D2S, D2L, D3 and D4. D2-like receptors do not appear adenylate cyclase-linked and may decrease intercellular cAMP levels.
Emerging understanding of the activities of neurologic mediators within the brain suggest that underlying dysfunctions may have behavioral manifestations. For example, D2-like receptors have been identified as potential targets for development of anti-psychotic agents and treatments for schizophrenia, based e.g., on antipsychotic effects of chlorpromazine but with resultant drug-induced Parkinson's symptoms and increased risk of tardive dyskinesia. Schizophrenia is (at present) believed to result from hyperactive dopaminergic transmission in the mesolimbic region of the brain. While antipsychotic drugs with fewer side-effects have been developed (e.g., haloperidol, fluphenazine, clozapine, olanzapine, risperidone), to date, no consensus antipsychotic dopaminergic antagonist pharmacologic or receptor profile has emerged and approaches under active consideration include: (i) combination approaches for blockade of D2-like and D1-like receptors as well as 5-HT2 and α1 adrenergic receptors, and (ii) selective approaches for blocking D2 subtypes, e.g., D3 and/or D4 or D2L/S and D4.
Unlike systemic treatments, neuraxial delivery of pharmaceutical agents may be complicated by endogenous mechanisms for recycling, scavenging and transporting neural mediators. For example, the Na+/Cl− dependent dopamine transporter, DAT1, granule system mediates calcium-dependent outward dopamine release into the synaptic cleft and inward energy-dependent dopamine vesicular re-uptake into the cytoplasm of presynaptic neurons. Loading of biosynthetic dopamine into granules is effected by the vesicular monoamine transporter (VMAT2; reviewed in Miller et al., 1999). DAT may also control movements of other monoamines in brain tissues. (Non-neuronal dopamine transporter uptake mechanisms may also exist, e.g., in kidney see Sugamori et al., 1999). Cocaine, amphetamines, phenyclidine and certain anti-depressants and uptake inhibitors provide examples of side-effects which may be encountered when dopamine transporter activity is interrupted (e.g., see Jones et al., 1999; Giros et al., 1992). DAT function may also be regulated by steroid hormones and transporter function has second order dependence on Na+ (Earles et al., 1999) and may be coupled (or uncoupled) to natural modulatory second messenger systems and ion channels, e.g., down-regulation accompanying activation of protein kinase C by phorbol esters (Melikian et al., 1999; reviewed in Figlewicz, 1999).
Pharmacological studies of DAT antagonists have suggested that, like the D1 receptor (supra), DAT transporters may be sensitive to N- and aromatic-ring substitutions with N-phenyl-substituted analogues inhibiting transport (Choi et al., 2000; Prakash et al., 1999; Husbands, et al., 1999). In addition, certain energetically unfavored boat conformations of rings may have relatively higher affinity for DAT (Prakash et al., 1999). Structural rearrangement of the DAT protein may be required for inward transport with loading being Na+ first, then dopamine and then Cl− (Chen et al., 2000).
Tissue enzyme systems for altering and inactivating hydroxyl-substituted aromatic amines and amides include oxioreductases, methylases and glucuronic acid conjugating enzyme systems. Monoamine oxidases, (i.e., MAO-A in neural tissues and MAO-B in other tissues including stomach and intestine), are oxioreductases that deaminate dopamine and other catecholamines with preferential activity manifest for 2-phenylethylamine and benzylamine. Catechol-O-methyltransferase is a cytosolic enzyme that catalyzes addition of a methyl group, usually at the 3 position of a benzene ring. O-methoxylated derivatives may be further modified by conjugation with glucuronic acid. Glucuronidation of catecholamine drug metabolites, i.e., involving hepatic glucuronosyltransferase and enzyme systems in kidney and intestine, have been reported in mammals and in the rat, dopamine glucuronides are reportedly present in cerebrospinal fluid (Wang et al., 1983). Several drugs investigated for dopaminergic agonists and antagonist properties are apparently metabolized and/or excreted as glucuronides, e.g., SCH23390 (a Schering prototype D1 receptor antagonist; Barnett, et al., 1992), CGS15873 (a Ciba-Geigy dopamine agonist; Leal et al., 1992), Carmoxirole (a Merck dopamine agonist; Meyer et al., 1992), Olanzapine (a Lilly dopaminergic compound; Mattiuz et al. 1997) and CP-93,393 (a Pfizer anxiolytic drug candidate; Prakash et al., 1998). Within this general class of cyclic Parkinson's drugs, it has been suggested that glucuronidation may be the mechanism targeting urinary and biliary excretion of phenolic drugs, e.g., see Mico et al., 1986 (indolone agonists); see Gerding et al., 1990 (N-0437, a tetralin agonist); see Wang et al., 1983 (catecholamines); see Green et al., 1996 (hydroxylated and carboxylated phenolic compounds); see Pocchiari et al., 1986 (Ibopamine); and see Claustre et al., 1990 and Alexander et al., 1984 (dopamine). Shindo et al., 1973 reportedly studied absorption of L- and D-dopa in vitro in ligated rat intestinal loops and found active transport and metabolism to dopamine glucuronides.
Certain cellular mechanisms for transporting glucose are known. For instance, intestinal intracellular transport vesicles containing Na+/glucose co-transporters (SGLTs) are known to drive active transport of glucose and galactose across the intestinal brush border by harnessing Na+ gradients across the membrane. Net rates of vesicle transport and exocytosis have been estimated to be in the range of 10 thousand to 1 million per second (Wright et al., 1997). Pointing out the essential nature of this transport, missense mutations in SGLT1 result in a potentially lethal inability to transport glucose and galactose (Martin et al., 1996). Specificity's and capabilities of transport are subjects of active current investigation (Mizuma et al., 1994). Antioxidant flavonol compounds are present in certain foods as glycosides and one recent study suggests that quercetin glucosides, a class of flavonols, may be transported across the rat small intestine via a glucose co-transporter pathway (Gee et al., 1998). Intestinal mechanisms for fructose and possible lactose absorption are currently less well understood. Unlike intestinal transport mechanisms, neural glucose transport at the blood brain barrier is reportedly mediated by endothelial cells and the sodium-independent facilitative transporter GLUT1 (Kumagai et al., 1999). At neuronal cells, glucose transport is reportedly mediated predominantly by GLUT3 (Vannucci, S. J. et al., 1998). Neural tissue is almost entirely dependent on glucose transport for normal metabolic activity because tissue stores of glucose are low (relative to demand).
The blood brain barrier effectively limits neuraxial delivery of many pharmaceutically active compounds, including dopamine. Approaches disclosed for delivering drugs to the brain include the following: namely, (i) lipophilic addition and modification of hydrophilic drugs, (e.g., N-methylpyridinium-2-carbaldoxime chloride; 2-PA; U.S. Pat. Nos. 3,929,813 and 3,962,447; Bodor et al, 1976, 1978 and 1981); (ii) linkage of prodrugs to biologically active compounds, (e.g., phenylethylamine coupled to nicotinic acid as modified to form N-methylnicotinic acid esters and amides, Bodor et al., 1981 and 1983; PCT/US83/00725; U.S. Pat. No. 4,540,564); (iii) derivatization of compounds to centrally acting amines (e.g., dihydropyridinium quaternary amine derivatives; PCT/US85/00236); (iv) caging compounds within glycosyl-, maltosyl-, diglucosyl- and dimaltosyl-derivatives of cyclodextrin (Bodor U.S. Pat. No. 5,017,566, issued May 21, 1991; Loftsson U.S. Pat. No. 5,324,718, issued Jun. 28, 1994 disclosing cyclodextrin complexes); and (v) enclosing compounds in cyclodextrin caged complexes (e.g., Yaksh et al., U.S. Pat. No. 5,180,716). However, these approaches suffer from various different disadvantages including poor pharmacokinetic half-life, poor neuraxial bioavailability, variable dosing and side effects.
Objects of the invention provide methods for neuraxial delivery of pharmaceutical agents as N-linked amine and amide glycoconjugates, including cyclic and heterocyclic prodrug compounds.